Diabetes affects 23.6 million people per year, with a total estimated cost of $174 billion. Of that cost, 50% is related to in-patient care. Insulin dependent type I diabetes mellitus (TIDM) can be controlled by exogenous insulin. However, poor management of TIDM, failure of the insulin pump to deliver insulin, or prior to a diagnosis of TIDM, glucose levels can rise drastically resulting in a condition called diabetic ketoacidosis (DKA).
DKA accounts for the majority of hospitalizations due to diabetes, especially in children, and accounts for 20% of all deaths related to diabetes (Krane, 1988). DKA is characterized by hyperglycemia (blood glucose levels greater than 250 mg/dL), acidosis (pH less than 7.3), and the presence of ketones in the urine. Patients usually present with dehydration, as seen by hypotension and decreased turgor, extreme thirst due to the high osmolarity of the blood, and in the late stages, vomiting and abdominal pain.
Diagnosing DKA includes assessing the level of consciousness, measuring blood samples for serum or plasma glucose levels, electrolytes, bicarbonate, pCO2, blood urea nitrogen (BUN), creatinine, pH, hemoglobin, and hematocrit (Wolfsdorf et al., 2007). Urinalysis for ketones and an ECG to check for cardiac abnormalities due to altered potassium ion (K+) levels also are monitored (Wolfsdorf et al., 2007). Therapy for DKA includes a correction of dehydration via normal saline (0.9% NaCl) over forty-eight hours, an insulin infusion at 0.1 U/kg/hr, and supportive cardiovascular and respiratory therapy, as needed.
Although these treatments are usually effective, about 0.5-3% of pediatric patients develop cerebral edema (CE), which has a mortality rate of up to 20% (Krane, 1988). For reasons unknown, CE occurs only in pediatric patients. Certain risk factors are associated with the development of CE, including an age of less than five years, severe acidosis as defined by a pH of less than 7.1, low pCO2, and a high BUN (Wolfsdorf et al., 2007). Once identified by the symptoms of headache, bradycardia, changes in neurological status, hypertension, and decreased O2 saturation, the treatment for CE induced by DKA must begin immediately (Vanelli and Chiarelli, 2003; Lam et al., 2005). Treatment includes intravenous mannitol 0.5-1 g/kg over twenty minutes, the reduction of fluid administration by one-third, the administration of a 3% hypertonic saline (5-10 mL/kg over thirty minutes), elevating the head of the bed, and supportive measures to maintain breathing. After the CE has subsided, a head CT scan should be obtained to rule out any neurological sequelae that may result in long term effects such as motor, speech, and learning deficits (Wolfsdorf et al., 2007).
The mechanism for the development of CE is unknown, but several hypotheses have been proposed including an osmotic disequilibrium between the brain and plasma, over-hydration and hyponatremia, intracerebral acidosis induced by alkali therapy (bicarbonate), and alterations in cerebral blood flow (Krane, 1988; Silver et al., 1997; Lam et al., 2005; Wolfsdorf et al., 2007; Yuen et al., 2008). Another possible theory is involvement of rapid insulin and rehydration therapy that leads to the development of CE and its complications, including neurogenic pulmonary edema and detrimental cardiovascular side effects, such as hypertension and increased heart rate (Sherry and Levitsky, 2008).
Endothelin (ET), a twenty-one amino acid vasoconstrictive peptide, elicits a wide range of activities in the body. ET contributes to physiological regulation of the cardiac, pulmonary, renal, and endocrine systems, as well as controlling blood flow to various organs of the body, such as the brain. There are three isoforms of ET: ET-1, ET-2 and ET-3, each of which binds to one of two G-protein coupled receptors, ETA or ETB (Yanagisawa et al., 1988a; Yanagisawa et al., 1988b; Gulati et al., 1997b). All isoforms bind with equal affinity to ETB, which is located on endothelial cells. ETA also binds all ET isoforms; however ET-1 and ET-2 bind equally and preferentially over ET-3. This receptor subtype is located on vascular smooth muscle cells (Said et al., 2005; Sasser et al., 2007).
All three isoforms act on varying physiological systems, and the effects of ET-1 have been studied extensively in diabetic states. Some studies report lower ET-1 levels in children with treated TIDM compared to non-diabetic controls, but other studies show an increase in ET-1 in TIDM patients (Malamitsi-Puchner et al., 1996; Vazquez et al., 1999). There is much conflicting evidence regarding the role of increased or decreased ET-1 and the development of complications associated with TIDM including hypertension, diabetic nephropathy, and stroke. Some studies associate elevated levels of ET-1 with hypertension, reduced renal function, age, and duration of the diabetic state, suggesting that high levels of ET-1 may be implicated in these common complications seen in diabetic patients (Haak et al., 1992). However, other studies show an elevated ET-1 level that does not correlate with hypertension and duration of disease (Takahashi et al., 1990; Schneider et al., 2002). It has been shown that insulin, exogenously or endogenously, increases ET-1 levels (Kirilov et al., 1994; Morise et al., 1995; Ferri et al., 1996). Although ET-1 studies in diabetic states show conflicting evidence regarding whether plasma levels of ET-1 are increased or decreased, it is clear that ET-1 does have an effect on insulin regulation.
In addition to the endocrine system, ET-1 has varying effects on the brain and cerebral vasculature, because increased levels of ET-1 are associated with vasoconstriction in the brain (Zhang et al., 2008). Several studies have shown that cerebral ischemia resulting from an increase in tone of the cerebral vasculature is positively correlated with an increase in ET-1. Increased intracranial pressure (ICP) also is associated with high levels of ET-1, as seen in stroke models of rats. The administration of an ETA blocking agent decreases ICP, showing a direct correlation with the development of ICP and ET (Lo et al., 2005). Additionally, ETA receptors have shown to be at increased activity during subarachnoid hemorrhage, which causes an increase in ICP (Lo et al., 2005). Blocking these receptors during increased ICP results in a neuroprotective effect during cerebral ischemia (Zhang et al., 2008). This again supports the observation that ET, specifically, ET-1 and ETA receptors, are involved in mediating brain blood flow.
Increased ET-1 levels also have been associated with neurogenic pulmonary edema, which can be reversed with BQ123, an ETA receptor antagonist (Bonvallet et al., 1994). In rats induced with neurogenic pulmonary edema, and the resulting side effects including metabolic acidosis, decreased pO2, increased pCO2, and systemic hypertension, increased levels of ET-1 were observed during a bronchoalveolar lavage. Upon administration of BQ123, the hypoxia and hypercapnea were ameliorated (Herbst et al., 1995). Another study demonstrated that intrathecal (IT) injection of ET-1 into rats resulted in intense pulmonary vasoconstriction, pulmonary edema (PE), and death in some cases. Pre-treatment with BQ123 prevented pulmonary edema and reduced the mortality rate by 50% (Poulat and Couture, 1998). Altered electrical physiological properties in rat myocytes resulting in cardiac arrhythmias have been displayed in rats with TIDM induced by streptozocin (STZ) (Ding et al., 2006). These studies support the theory that increased ET-1 is involved in both CE and PE, and that the administration of an ET antagonist will reduce its resulting side effects of systemic hypertension, hypercapnea, and hypoxia.
ET antagonists are currently being used in research and in clinical application. Many ET antagonists used in the laboratory setting, including BQ-123, BMS-182874, and PD-156707, are ETA receptor antagonists. BQ-788 and BQ-3020 are selective ETB antagonists. TAK-044 is a non-selective ET antagonist, blocking the effects of both ETA and ETB receptors. Bosentan, a non-selective ET-1 antagonist, blocks the ETA and ETB receptors and is currently being used to treat pulmonary hypertension.